The comparison between intradermal injection of abobotulinumtoxina and normal saline for face-lifting: a split-face randomized controlled trial

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1 Original Contribution Journal of Cosmetic Dermatology, 15, The comparison between intradermal injection of abobotulinumtoxina and normal saline for face-lifting: a split-face randomized controlled trial Rungsima Wanitphakdeedecha, MD, MA, MSc, 1 Chanida Ungaksornpairote, MD, 1 Arisa Kaewkes, MD, 1 Viboon Rojanavanich, MD, 2 Weeranut Phothong, MD, 1 & Woraphong Manuskiatti, MD 1 1 Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand 2 Bangkok Christian Hospital, Bangkok, Thailand Summary Background Botulinum toxin type A (BTA) has been approved for the treatment of strabismus, blepharospasm, muscle spasm, cervical dystonia, pain syndrome, glabella wrinkles, and severe primary axillary hyperhidrosis. Intradermal injection of BTA has been used off-label by many clinicians for the purpose of face-lifting effect. Few studies on onabotulinumtoxina (ONA) demonstrated no clinical efficacy on facelifting effect when comparing to normal saline solution (NSS). So far, there is no split-face comparison study on face-lifting effect of abobotulinumtoxina (ABO). Objective To determine the face-lifting effect of ABO intradermal injection and NSS. Methods Twenty-two subjects with symmetrical faces on both facial expression and expressionless were randomly injected with ABO at 1:7 cc dilution (500 unit or one vial in 7 cc of NSS) on one side and NSS on the other side using intradermal injection technique. Standardized photographic documentation was obtained at baseline, and at 2 weeks after treatment. The face-lifting effect was graded by two blinded dermatologists using photographic comparison and rated by the patients. Side effects were also recorded at the end of the study. Results Face-lifting effect was demonstrated in 40.9% and 4.5% of patients with ABO and NSS, respectively. There was a statistically significant difference in face-lifting effect when comparing between ABO and NSS (P = 0.021). The face-lifting was reported in 50.0% of patients receiving ABO injection. The patients with oval-face shape tended to respond better with ABO (P = 0.046). The odd of face-lifting effect for patients aged younger than 32 was higher than patients aged older than 32 with the odds ratio of 7.9 and 95% confidence interval of Facial asymmetry was found in 22.7% of subjects. Conclusions This study demonstrated the face-lifting effect of ABO intradermal injection. Patients with oval-face shape and aged younger than 32 tended to respond better. Therefore, patient selection should be emphasized to improve efficacy of this technique. Keywords: intradermal injection, abobotulinumtoxina, face-lifting Correspondence: Rungsima Wanitphakdeedecha, Associate Professor, Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Pran-nok Road, Bangkok 10700, Thailand. rungsima.wan@mahidol.ac.th The copyright line for this article was changed on 03 November 2016 after original online publication. Accepted for publication September 1, 2016 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made The Authors. Journal of Cosmetic Dermatology Published by Wiley Periodicals, Inc.

2 Introduction Facelift surgery has been introduced to treat facial laxity to give a more youthful facial appearance. 1 However, complications following facelift surgery including hematoma, surgical scars, and infection, have been reported. 2 Less-invasive approach has been employed, for example, laser and light-based devices, monopolar radiofrequency, and microfocused ultrasound with variable results. 3 Botulinum toxin type A (BTA) has been approved for the treatment of strabismus, blepharospasm, muscle spasm, cervical dystonia, pain syndrome, glabella wrinkles, and severe primary axillary hyperhidrosis. 4 The other off-label uses for cosmetic purposes have been utilized for texture and contouring improvement. 5 Currently, BTA is used in temporal brow lifting by reducing the activity of superolateral part of orbicularis oculi muscle resulting in lateral brow elevation. 6 Oral commissure and jowl lifting can also be performed by injecting BTA into depressor anguli oris and plastyma muscle, respectively. 7 This technique was based on the imbalance of facial muscles by weakening the depressor muscles allowing the levator muscles to contract resulting in midface-lifting. 8 Recently, BTA has been tried by many clinicians for the other off-label indication of face-lifting effect using intradermal or subdermal injection of very diluted BTA and claimed that the face-lifting could be seen immediately after treatment. Multiple tiny aliquots of a more diluted concentration of BTA than traditional dilution were injected into dermis or between dermis and superficial layer of muscles over the area that lifting was needed. Few split-face comparison studies on OnabotulinumtoxinA (ONA) demonstrated no clinical efficacy on facelifting effect when comparing to normal saline solution (NSS) using intradermal injection technique. 9,10 Until now, there is no split-face comparison study on facelifting effect of abobotulinumtoxina (ABO). Therefore, the objective of this study was to determine the facelifting effect of ABO intradermal injection and NSS. Methods Twenty-two subjects with symmetrical faces on both facial expression and expressionless were enrolled into this study. All subjects had mild facial skin laxity with grading score of and aged ranging from 20 to 50 years. 11 Patients who were pregnant or lactating, who received BTA injections or other cosmetic procedures in the preceding 12 months, who had history of human albumin or cow s milk protein allergy, underlying diseases of any neuromuscular diseases such as atrophy or weakness of palmar muscle, myasthenia gravis or amyotrophic lateral sclerosis were excluded from this study. This was a split-face, randomized, double-blind control study. Topical anesthetic cream with 5% lidocaine and prilocaine (Racser â, Galentic Pharma Pvt. Ltd, Mumbai, India) was applied on subjects faces for 1 h before starting procedure. After topical anesthetic cream was removed, all subjects were randomly injected on one side of their face with ABO (Dysport â, Ipsen, UK) at 1:7 cc dilution (a vial of 500 U of ABO was reconstituted with 7 ml of sterile, preservative-free NSS) and with 0.9% NSS on the other side in the same amount of volume by a blinded injector. All subjects were treated with a well-trained injector using an intradermal injection technique using 1-cc syringe and 31-gauge needle. At each injection site, a small amount of solution, approximately 0.04 cc, was injected into dermis or between dermis and superficial layer of muscles over the area that lifting was needed to create a wheal cm in diameter. The illustration of injection sites was shown in Figure 1. For upper face-lifting, the superior portion of frontalis muscles just below the hairline and corrugator supercilii muscles was injected. In addition, the lateral part of orbicularis oculi and plastyma muscles was also treated for midface-lifting. To evaluate the immediate effect of ABO on face-lifting, the blinded injector was asked to evaluate the face-lifting on both sides of patients faces and guess which side received ABO treatment. All subjects were asked to avoid sauna, laser or energy-based devices treatment, and facial massage for 2 weeks after injection. Photographic documentation using identical camera settings, lighting, and patient positioning was obtained at baseline and 2 weeks after injection. Independent clinical assessments of face-lifting and wrinkles soothing were conducted by two blinded dermatologists evaluations of comparative photographs using quartile grading scale (0 = no improvement, 1 = 1 25% improvement, 2 = 26 50% improvement, 3 = improvement, and 4 = % improvement) at the end of the study. During evaluation, the two evaluators were also blinded to the order of the photographs. Pretreatment and post-treatment photographs of each individual subject were displayed on a liquid crystal display (LCD) monitor. The evaluators were then asked to perform two actions. First, they were asked to identify the photograph that showed better improvement of skin laxity and wrinkles. Second, the evaluators rated the improvement of skin laxity and wrinkles in the two photographs using the following numeric responses: 1 25%, 25 50%, The Authors. Journal of Cosmetic Dermatology Published by Wiley Periodicals, Inc. 453

3 Figure 1 The Illustration demonstrating injection sites for intradermal ABO injection for face-lifting purpose. 75%, and % improvement. If the evaluators identified the pretreatment photograph as having better skin laxity or wrinkles appearance, the assessment was recorded as worse. When the evaluators identified the post-treatment photograph as having better skin laxity or wrinkles appearance, those quartile grading scales reflected an improvement in skin laxity and wrinkles. Patient evaluation survey was also recorded at the end of the study. The patients we asked to guess which side received ABO treatment and evaluated the improvement of skin laxity and wrinkles using quartile grading scale mentioned previously. Side effects were also assessed at the end of the study. The differences of skin laxity and wrinkles improvement were compared between ABO and NSS group using Wilcoxon signed-rank test. Subgroup analysis of ABO group was performed using Fisher s exact test. All data were analyzed using a statistical analysis software (SPSS version 18.0; SPSS Inc, Chicago, IL, USA). The statistically significant was defined by P-value < This study was approved by the Ethical Committee on Research Involving Human Subjects, Faculty of Medicine, Siriraj Hospital, Mahidol University, and conformed to the guidelines of the 1975 Declaration of Helsinki. Written informed consent was obtained from all study subjects. Results Of all 22 subjects, everyone completed treatments and attended 2-week follow-up visits. Among them, there were 21 (95.5%) female and one (4.5%) male patients ranging in age from 22 to 42 years (mean age = 31.5 years, standard deviation = 5.5 years). Most of patients had oval facial shape (72.7%) while 27.3% had chubby face. A total unit of ABO used was varied among individual subject ranging from 120 to 180 units per one side of the face. Immediately after treatment, the blinded injector could identify the site that was treated with ABO correctly in 11 (50.0%) cases. The lifting effect evaluated by two blinded investigators was found in nine (40.9%) and one (4.5%) subjects on the side that was treated with ABO and NSS, respectively, at 2 weeks after injection. There was a statistically significant difference in face-lifting effect when comparing between ABO and NSS (P = 0.021). Of all nine cases demonstrating face-lifting after ABO treatment, seven (77.8%) cases were rated to have 1 25% improvement, whereas two (22.2%) cases showed 26 50% improvement (Fig. 2). The wrinkles soothing effect evaluated by two blinded investigators was found only in two (9.1%) subjects on the side that was treated with ABO at 2 weeks after injection. And both of them were rated to have 1 25% improvement. To identify the factors influenced the face-lifting effect, subgroup analysis on ABO-treated site was performed. The patients with oval-face shape tended to respond better with ABO (P = 0.046). In addition, the odd of face-lifting effect for patients aged younger than 32 was higher than patients aged older than 32 with The Authors. Journal of Cosmetic Dermatology Published by Wiley Periodicals, Inc.

4 Figure 2 Clinical improvement of skin laxity of a representative case at 2 weeks after injection was demonstrated. This subject was rated to have 25 50% improvement on the site that was treated with ABO. Figure 3 Facial asymmetry as the side effect of ABO injection. the odds ratio of 7.9 and 95% confidence interval of In contrast, the dosage of ABO has no influence on clinical result of face-lifting. According to patient evaluation survey, 12 (54.5%) subjects noticed the difference between the left and right sides of their face. Of all 22 subjects, 11 (50.0%) could identify the site that was treated with ABO correctly by the improvement of skin laxity. Of all 11 cases demonstrating face-lifting effect after ABO treatment, five (45.5%), five (45.5%), and one (9.1%) cases rated to have 1 25%, 26 50%, and 51 75% improvement, respectively. The wrinkles soothing effect evaluated by patients was found only in nine (40.9%) subjects on the side that was treated with ABO at 2 weeks after injection. Of all nine cases demonstrating wrinkles soothing effect after ABO treatment, two (22.2%), six (66.7%), and one (11.1%) cases rated to have 1 25%, 26 50%, and 51 75% improvement, respectively. None of the patients experienced severe adverse effects, such as allergic reaction, facial palsy, or severe paralysis of muscles adjacent to the point of injection. Facial asymmetry was found in five (22.7%) subjects. Among these, three (13.6%) developed mild degree of brow ptosis, and two (9.1%) subjects demonstrated asymmetrical smiling (Fig. 3) The Authors. Journal of Cosmetic Dermatology Published by Wiley Periodicals, Inc. 455

5 Discussion Recently, many off-label cosmetic uses of BTA have been introduced. 12 Intradermal injection of BTA was the other technique that has been used off-label by many clinicians for the purpose of face-lifting effect. However, the proper use of this technique remains a challenge due to lack of evidence-based supporting clinical study. The result of face-lifting effect following intradermal BTA injection has been claimed to cause by increasing collagen synthesis. 9 As this procedure could be performed by injecting multiple tiny aliquots of a more diluted concentration of BTA than traditional dilution into dermis, the collagen production found after treatment may probably cause by needle pricks, not BTA itself. 10 In addition, few split-face comparison studies on OnabotulinumtoxinA (ONA) demonstrated no clinical efficacy on face-lifting effect when comparing to normal saline solution (NSS) using intradermal injection technique. 9,10 To the best of our knowledge, this was the first study to compare the face-lifting effect of ABO intradermal injection and NSS. Even though, we found that there was a statistically significant difference in face-lifting effect when comparing between ABO and NSS. However, patients with oval-face shape and aged younger than 32 tended to respond better. Therefore, patient selection should be emphasized to improve efficacy of this technique. Some injectors claimed that the face-lifting effect from ABO intradermal injection could be seen immediately after treatment resulting from prompt fibroblast contraction without any supporting evidence. To evaluate the immediate effect of ABO on face-lifting, the blinded injector was asked to evaluate the face-lifting on both sides of patients faces and guess which side received ABO treatment. Unfortunately, the blinded injector could identify the site that was treated with ABO correctly only in 50.0% of cases which was equal to the chance of choosing the correct answer at random. This finding demonstrated that immediate facelifting after ABO treatment could not be identified. Therefore, the immediate face-lifting effect found by some injectors might result from the volume effect from solution that has been injected at multiple sites or from the swelling effect of the skin at the injection site from multiple needle pricks. 13 The main limitation of this study was small sample size. Increasing number of sample size might impact the statistically significant difference in face-lifting effect when comparing between ABO and NSS. Thus, the study with larger number may need to be conducted to verify this finding. The additional limitation of this trial is that it was limited to photographic analysis. As BTA effected on both dynamics and emotional facial expression, 14 photographic evaluation might not be enough to demonstrate the improvement of both skin laxity and wrinkles. In summary, this study demonstrated the face-lifting effect of ABO intradermal injection. Patients with ovalface shape and aged younger than 32 tended to respond better. Therefore, patient selection should be emphasized to improve efficacy of this technique. In addition, the further study with larger number of patients and proper method of evaluation should be carried out to verify these findings. Acknowledgments This research project is supported by Faculty of Medicine Siriraj Hospital, Mahidol University. The authors wish to thank Ms. Phassara Klamsawat and Ms. Phonsuk Yamlexnoi for their assistance in recruiting subjects and managing the database. References 1 Bloom D, Immerman B, Rosenberg B. Face-lift complications. Facial Plast Surg 2012; 28: Chaffoo RA. Complications in facelift surgery: avoidance and management. Facial Plast Surg Clin North Am 2013; 21: Jerdan K, Fabi S. A noninvasive approach to off-face skin laxity and tightening: a review of literature. Semin Cutan Med Surg 2015; 34: Lew F. Review of the FDA-approved uses of botulinum toxins, including data suggesting efficacy in pain reduction. Clin J Pain 2002; 18 (6 Suppl): S Small R. Botulinum toxin injection for facial wrinkles. Am Fam Physician 2014; 90: Uygur S, Eryilmaz T, Bulam H et al. The quantitative effect of botulinum toxin A over brow height. J Craniofac Surg 2013; 24: Goldman A, Wollina U. Elevation of the corner of the mouth using botulinum toxin type A. J Cutan Aesthet Surg 2010; 3: Petchngaovilai C. Midface lifting with botulinum toxin: intradermal technique. J Cosmet Dermatol 2009; 8: Chang SP, Tsai HH, Chen WY et al. The wrinkles soothing effect on the middle and lower face by intradermal injection of botulinum toxin type A. Int J Dermatol 2008; 47: Kapoor R, Shome D, Jain V et al. Facial rejuvenation after intradermal botulinum toxin: Is it really the botulinum toxin or is it the pricks? Dermatol Surg 2010; 36 (Suppl 4): The Authors. Journal of Cosmetic Dermatology Published by Wiley Periodicals, Inc.

6 11 Alexiades-Armenakas M. A quantitative and comprehensive grading scale for rhytides, laxity and photoaging. J Drugs Dermatol 2006; 5: Noland ME, Lalonde DH, Yee GL et al. Current uses of botulinum neurotoxins in plastic surgery. Plast Reconstr Surg 2016; 138: 519e 30e. 13 Ozdemir M, Bodur S, Engin B et al. Evaluation of application of multiple needle pricks on the pathergy reaction. Int J Dermatol 2008; 47: Michaud T, Gassia V, Belhaouari L. Facial dynamics and emotional expressions in facial aging treatments. J Cosmet Dermatol 2015; 14: The Authors. Journal of Cosmetic Dermatology Published by Wiley Periodicals, Inc. 457